The overall objective of this program is to identify candidate medications that may function as pharmacological replacements for abused stimulants Synthetic efforts, conducted by H M Deutsch, Ph D , Georgia Institute of Technology, focus on derivitization of two indirect dopamine agonists, methylphenidate and the novel bicyclooctane LR-5182 The aim is to modify the structures of these compounds to generate potent, long-lasting drugs that substitute for cocaine and may thus prevent craving and withdrawal symptoms induced by drug abstinence (analogous to methadone for the treatment of heroin abuse) During the last project period we evaluated several structural derivatives of methylphenidate for their capacity of mimic the discriminative stimulus effects of cocaine in a manner predictive of cocaine-like subjective effects Monkeys were trained to discriminate a behaviorally active dose of cocaine (0 3 mg/kg, i m ) from vehicle using a two-choice drug discrimin ation pro cedure Under test conditions, cocaine, methylphenidate and a number of N-substituted and aromatic ring-substituted derivatives of methylphenidate induced dose-related increases in drug-appropriate responding reaching r 90% responses on the cocaine-associated lever Of these compounds dichloromethylphenidate, dichlororitalinol and dichlororitalinol methyl ester were more potent and had slower onsets and longer durations of action compared either cocaine or methylphenidate, suggesting that they may be suitable candidates for further evaluation in drug self-administration studies scheduled for the forthcoming year